The digitalis-derived steroid glycosides have been among the most widely-prescribed drugs. Digoxin today is the most favored digitaloid in the clinic and is extensively used to treat certain cardiac dysfunctions. The cardiac glycosides bind with high affinity and high specificity to a Na.sup.+ - and K.sup.+ -transporting ATPase. It is generally accepted that inhibition of this cellular enzyme by the cardiac glycosides initiates a series of events in the cardiac muscle that lead to increased contractility.
Weiland et al in J. Enz. Inhib. 2:31 to 36, 1987 have described the effect of forming glycosides of chloramidone acetate (CMA). It had previously been observed that CMA had a high affinity for Na/K-ATPase but causes cardiodepression or decreased contractility, which overrides any positive effects on contractility that otherwise result from inhibition of the Na.sup.+ /K.sup.+ pump. Certain glycoside derivatives of CMA, namely the arabinofuranoside and the rhamnoside derivatives, are described by Weiland et al and were tested for Na.sup.+ /K.sup.+ -ATPase inhibition and in vivo inotropic activity, in comparison with the hydroxy derivatives of CMA and digoxin.
A decreased potency for the glycosides was observed when compared to the hydroxy derivative of CMA and digoxin (itself a glycoside) but the glycosides increased contractility, in comparison with the depressive action of CMA. High doses of the glycoside did not induce arrhythmias, in contrast to the effect of digoxin at high dose levels.
In a publication in The Pharmacologist, 29:135, (1987), Halpryn et al, there is described the provision of another glycoside derivative of a pregnane, namely 3.beta.-rhamnosyloxy-14.beta.-amino-5.beta.-pregnane-20.beta.-ol. The effect on cardiac contractility of this compound and digoxin were compared and the new compound was found to be superior, in terms of tolerance to higher dosage. This compound is as potent as the cardiac glycosides, as disclosed by Schonfeld et al, Arch. Pharmacol. 329:414-426, 1985.
An extensive study has been conducted by the inventors with respect to a wide series of steroids of the pregnane and androstane type. The potencies of these steroids were determined in a .sup.3 H-ouabain radioligand binding assay (RBA). Past experience has indicated to the inventors that the potency of the steroids to displace the labelled cardiac glycoside (i.e. ouabain) in the assay parallel their biological activity, that is their cardiac glycoside-like activity in the ability to inhibit Na/K-ATPase and elicit characteristic cellular response.